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Jia J.-B.,Fudan University | Jia J.-B.,Shenzhen Kangzhe Pharmaceutical Co. | Wang W.-Q.,Fudan University | Sun H.-C.,Fudan University | And 11 more authors.
Investigational New Drugs | Year: 2011

Previous studies have demonstrated that tyroserleutide (YSL) inhibits tumor growth in an animal model of hepatocellular carcinoma (HCC). However, its effects on HCC metastasis are still not fully understood. To examine YSL as a novel agent to prevent HCC metastasis, a metastatic human HCC orthotopic nude mouse model of MHCC97L was used. The antitumor and antimetastasis effects of YSL were also evaluated in combination with radiation. Hypoxia and epithelial-mesenchymal transition (EMT)-related molecules were studied. YSL inhibited MHCC97L cell invasion in vitro with or without irradiation. YSL did not significantly inhibit tumor growth but decreased pulmonary metastasis and prolonged life-span for more than 40 days, which correlated with down-regulation of matrix metalloproteinase-2. Radiotherapy inhibited early-stage tumor growth and promoted tumor hypoxia. The re-implanted tumor volume in the radiotherapy group was not significantly different from the control, in which the incidence of lung metastasis increased after radiotherapy (6/6 versus 3/6, P=0.046); however, YSL inhibited the growth of re-implanted tumor after radiotherapy. Furthermore, YSL at 160 or 320 μg/kg/day almost completely inhibited lung metastasis induced by irradiation (1/6 versus 6/6, P=0.002 for both dosages). YSL down-regulated hypoxia-inducible factor 1α (HIF-1α) and transmembrane protease serine 4 ( ™PRSS4), and inhibited EMT was associated with the antimetastasis capability of YSL. Our data suggest that YSL inhibits the enhanced invasiveness and metastatic potential of HCC induced by irradiation through down-regulation of HIF-1α and ™PRSS4 and inhibition of EMT. YSL may have potential as a new antimetastasis agent for radiotherapy. © Springer Science+Business Media, LLC 2010. Source


Jian X.,Tianjin Medical University | Fu Z.,Tianjin Medical University | Zhang Y.,Tianjin Medical University | Che X.,Tianjin Medical University | And 2 more authors.
Experimental and Therapeutic Medicine | Year: 2012

Tyroserleutide (YSL) is a tripeptide compound that exhibits potent antitumor activity in human tumor xenografts and tumor cell lines. However, the target of YSL on which it exerts its antitumor activity has yet to be identified. Therefore, our study aimed to investigate the subcellular location of YSL in BEL-7402 human hepatocellular carcinoma cells. Using methods of fluorescent tracing and confocal colocalization, we provide evidence that when BEL-7402 cells are treated with YSL, YSL is distributed in the cytoplasm and colocalized with the mitochondria of cancer cells. Furthermore, we observed the effect of YSL on the isolated mitochondria. Using fluorescence spectrophotometry to monitor the Δψ collapse of mitochondria isolated from BEL-7402 cells by reversion of the quenching of tetramethylrhodamine methyl ester (TMRM), we found that the isolated mitochondria reversed the quenching of the fluorescence in the solution containing TMRM and YSL. This indicates that YSL decreases the Δψ of the isolated mitochondria. Another photometry method was used to observe the effect on mitochondrial swelling when YSL acted directly on the isolated mitochondria. We reveal that YSL directly causes mitochondrial swelling in 60 min. In conclusion, this study encloses a preliminary facet of the pharmacological target of YSL, and we speculate that YSL may act directly on the mitochondria to exert its antitumor activity. Source


Li Y.,China Pharmaceutical University | Li Y.,Shenzhen Kangzhe Pharmaceutical Co. | Yang H.,National Institutes for Food and Drug Control NIFDC | Liao H.,National Institutes for Food and Drug Control NIFDC | And 4 more authors.
Journal of Chromatography B: Analytical Technologies in the Biomedical and Life Sciences | Year: 2013

A selective and sensitive ultra-performance liquid chromatography-electrospray ionization tandem mass spectrometry (UPLC-MS) method was developed for the simultaneous determination of ten biogenic amines (tryptamine, 2-phenylethylamine, putrescine, cadaverine, histamine, tyramine, spermidine, adrenaline, dopamine and spermine) in a thymopolypeptides injection from the Chinese market for the first time. Biogenic amines (BAs) were pre-column derivatised by dansyl chloride after direct sample dilution. Dansylated amines were separated on an ACQUITY UPLC BEH Shield RP18 column (2.1. mm. ×. 150. mm I.D., 1.7. μm) using a gradient elution. Quantification was done by monitoring fragment ions of each derivative under the MS mode of multiple reaction monitoring (MRM). A satisfactory result of method validation was obtained. The linearity ranged from 0.32 to 1182.9. μg/L and the correlation coefficients (r) for all amines were above 0.99. The LOD ranged from 0.08. μg/L for 2-phenylethylamine and tyramine to 8.00. μg/L for adrenaline; the LOQ ranged from 0.32. μg/L for 2-phenylethylamine to 12.12. μg/L for dopamine. The recovery ranged from 75.8 to 110.3% after spiking standard solutions of BAs to a sample at three levels. The intra and inter-day precision RSD were 0.78-8.85% and 1.39-9.93% respectively. Eighty-four injections were analyzed by this method. Nine biogenic amines were found in them except adrenaline. Moreover, the relationship between the result of test for depressor substances and the content of BAs was statistically analyzed. © 2013 Elsevier B.V. Source


Che X.,Tianjin Medical University | Hu J.,Tianjin Medical University | Lin G.,Shenzhen Kangzhe Pharmaceutical Co. | Lu R.,Tianjin Medical University | And 3 more authors.
Molecular and Cellular Biochemistry | Year: 2011

Peptide deformylase (PDF) is considered an attractive target for screening novel antibiotics. The PDF from Escherichia coli and Staphylococcus aureus are representative of the gram-negative species type of PDF (type I PDF) and the gram-positive species type of PDF (type II PDF), respectively. They could be used for screening broad-spectrum antibiotics. Herein, we cloned the def gene by PCR, inserted it into plasmid pET-22b-def, and transformed the plasmid into E. coli BL21 (DE3) cells, then the cells were induced by IPTG to express PDF. E. coli Ni2+-PDF was extracted and purified by ion-exchange chromatography and gel filtration chromatography. S. aureus PDFs were extracted and purified using the MagExtractor kit. The nickel form of S. aureus PDF was obtained by adding NiCl2 to all reagents used for purification. Iron-enriched S. aureus PDF was obtained by adding FeCl3 to the growth medium for E. coli BL21 (DE3) cells and adding FeCl3 and catalase to all reagents used for purification. The activities of PDFs were analyzed, compared, and grouped according to the experimental conditions that produced optimal activity, and we used actinonin as an inhibitor of PDF and calculated the IC50 value. We obtained high expression of E. coli and S. aureus PDF with high activity and stability. The function of PDFs was inhibited by actinonin in a dosedependent manner. Results may be helpful for future mechanistic investigations of PDF as well as high-throughput screening for other PDF inhibitors. © Springer Science+Business Media, LLC. 2011. Source


Wang L.,Tianjin Medical University | Wang S.,Tianjin Medical University | Lu R.,Tianjin Medical University | Lu R.,Shenzhen Kangzhe Pharmaceutical Co. | And 10 more authors.
Transplant Immunology | Year: 2010

The pentapeptide PLNPK (Pro-Leu-Asn-Pro-Lys) is extracted from the spleen. Preliminary studies have shown that PLNPK could inhibit T lymphocyte transformation and antibody production. In the present study, we detected the inhibitory effect of PLNPK on one-way mixed leukocyte reaction (MLR) in vitro and observed the effect of PLNPK on the duration of allograft survival in mouse models of skin or cardiac transplantation. Pathological damage and T cell infiltration of the grafts were also detected. Results showed that PLNPK could significantly inhibit T lymphocyte proliferation, with an optimized inhibition of 40%. Also PLNPK could significantly prolong the mean survival time of skin allograft and cardiac allograft, producing survival rates of 42% and 38.7%, respectively. PLNPK at a dose of 200 μg/kg/d or 100 μg/kg/d could significantly suppress ConA-induced T cell proliferation and T cell IL-2 secretion in transplant recipient mice, compared to the saline group (P<0.05). This information suggests that PLNPK can effectively antagonize transplant rejection, possibly by reducing IL-2 secretion by T cells and inhibiting T cell proliferation and activation. © 2010 Elsevier B.V. Source

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